Nuclear Targeting of Mutant Huntingtin Increases Toxicity

Huntington's disease is a neurodegenerative disorder resulting from expansion of the polyglutamine region in huntingtin. Although huntingtin is normally cytoplasmic, in affected brain regions proteolytic fragments of mutant huntingtin containing the polyglutamine repeat form intranuclear inclus...

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Bibliographic Details
Published in:Molecular and cellular neuroscience 1999-08, Vol.14 (2), p.121-128
Main Authors: Peters, Matthew F., Nucifora, Frederick C., Kushi, Jonathan, Seaman, Holly C., Cooper, Jillian K., Herring, William J., Dawson, Valina L., Dawson, Ted M., Ross, Christopher A.
Format: Article
Language:English
Subjects:
Animals
Cell Nucleus - pathology
Cell Nucleus - physiology
Cell Survival
Humans
Huntingtin Protein
Huntington Disease - genetics
Mice
Nerve Tissue Proteins - chemistry
Nerve Tissue Proteins - genetics
Nerve Tissue Proteins - physiology
Neuroblastoma
Neurotoxins
Nuclear Proteins - chemistry
Nuclear Proteins - genetics
Nuclear Proteins - physiology
Recombinant Proteins - chemistry
Recombinant Proteins - metabolism
Transfection
Tumor Cells, Cultured
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Summary:Huntington's disease is a neurodegenerative disorder resulting from expansion of the polyglutamine region in huntingtin. Although huntingtin is normally cytoplasmic, in affected brain regions proteolytic fragments of mutant huntingtin containing the polyglutamine repeat form intranuclear inclusions. Here, we examine the contribution of nuclear localization to toxicity by transiently transfecting neuro-2a cells with an N-terminal huntingtin fragment similar in size to that believed to be present in patients. The huntingtin fragment, HD-N63, was targeted either to the cytoplasm with a nuclear export signal (NES) or to the nucleus with a nuclear localization signal (NLS). The NES decreased the number of cells with aggregates in the nucleus while an NLS had the opposite effect. By cotransfecting HD-N63 with GFP as a marker, we observed direct cell loss with constructs containing expanded polyglutamine repeats. Compared to unmodified HD-N63–75Q, adding an NES reduced cell loss by 57% while an NLS increased cell loss by 111%. These results indicate that nuclear localization of mutant huntingtin fragments plays an important role in cell toxicity.
ISSN:1044-7431
1095-9327
DOI:10.1006/mcne.1999.0773